4-aryl-5-pyrimidine imiazole substituted compounds

ABSTRACT

The present invention relates to a novel method for synthesizing imidazole derivatives having 4-aryl, 5-pyrimidine heterocyclic rings using a novel cycloaddition reaction.

This application claims the benefit of provisional application Ser. No. 60/009,098 filed Dec. 22, 1995.

FIELD OF THE INVENTION

The present invention relates to a novel method for synthesizing imidazole derivatives having 4-aryl, 5-pyrimidine heterocyclic rings.

BACKGROUND OF THE INVENTION

The present invention describes a novel, and general method to prepare 5-pyrimidinyl substituted imidazoles. Previous syntheses of is class of molecules utilized the van Leusen reaction (van Leusen, A.M., et. al. J. Org. Chem. 1977, 42, 1153), which involves the cycloaddition of an imine and a tosylisonitrile. Difficulties in preparing the aldehyde precursors to the desired imines limited the scope of this approach. In Adams et al., WO 95/02591 an improvement on the cycloaddition reaction is shown for similar compounds. However addition of a pyrimidine rig in an environmentally favourable and commercially feasible manner is still needed. The present invention employs a novel method of cycloaddition of a tosylisonitrile with an α-ketoaldimine to produce a 5-keto imidazole derivative. The 5-keto group serves as an excellent precursor for addition of the optionally substituted pyrimidine ring.

SUMMARY OF THE INVENTION

The present invention is to a process of making compounds of Formula (I), ##STR1## wherein R₁ is an optionally substituted pyrimidin-4-yl ring;

R₄ is an optionally substituted phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl ring;

m is 0, or the integer 1 or 2;

m' is an integer having a value of 1 or 2,

R₂ is -(CR₁₀ R₂₀)_(n') (OR₉, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀ -alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroaryl-C₁₋₁₀ -alkyl, (CR₁₀ R₂₀)_(n) OR ₁₁, (CR₁₀ R₂₀)_(n) S(O))_(m) R₁₈, (CR₁₀ R₂₀)_(n) NHS(O)₂ R₁₈, (CR₁₀ R₂₀)_(n) NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NO₂, (CR₁₀ R₂₀)_(n) CN, (CR₁₀ R₂₀)_(n') SO₂ R₁₈, (CR₁₀ R₂₀)_(n) S(O)_(m') NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) C(Z)R₁₁, (CR₁₀ R₂₀)_(n) OC(Z)R₁₁, (CR₁₀ R₂₀)_(n) C(Z)OR₁₁, (CR₁₀ R₂₀)_(n) C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) C(Z)NR₁₁ OR₉, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)R₁₁, (CR_(10R) ₂₀)_(n) NR₁₀ C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)R₁₁, (CR₁₀ R₂₀)_(n) C(═NOR₆)R₁₁, (CR₁₀ R₂₀)_(n) NR₁₀ C(═NR₁₉)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) OC(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or 4-(R₁₂)-5-(R₁₈ R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroamyl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted;

n is an integer having a value of 1 to 10;

n' is 0, or an integer having a value of 1 to 10;

Z is oxygen or sulfur;

R₃ is heterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈ ;

R₆ is hydrogen, a pharmaceutically acceptable cation, C₁₋₁₀ alkyl, C₃₋₇ cycloalyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aryl, or C₁₋₁₀ alkanoyl;

R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₂₋₁₀ C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀ R₂₀ D)_(n) OR₁₁, (CR₁₀ R₂₀)_(n) S(O)_(m) R₁₈, (CR₁₀ R₂₀)_(n) NHS(O)₂ R₁₈, (CR₁₀ R₂₀)_(n) NR₁₃ R₁₄ ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;

R₉ is hydrogen, --C(Z)R₁₁ or optionally substituted C₁₋₁₀ alkyl, S(O)₂ R₁₈, optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl;

R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl;

R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl;

R₁₂ is hydrogen or R₁₆ ;

R₁₃ and R₁₄ is each independently selected from hydrogen or optionally substituted C₁₋₄ alkyl, optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉ ;

R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇ cycloalkyl;

R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C₁₋₁₀ alkyl, heteroaryl or heteroarylalkyl; and

R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl;

which process comprises:

a) reacting a compound of formula (II), as defined below ##STR2## wherein R is the optional substituent on the pyrimidinyl (R₁) moiety in Formula (I), or is hydrogen, an optionally substituted alkyl or an optionally substituted aryl, with a compound of the Formula R₂ NH₂ (III), wherein R₂ is as defined for Formula (I), to yield a compound of Formula (IV) ##STR3## wherein R and R₂ are as defined above; and b) reacting a compound of Formula (IV) with a compound of Formula (V) and a suitable base, ##STR4## wherein Ar is an optionally substituted aryl; and R₄ is as defined for Formula (I); to yield a compound of Formula (VI) ##STR5## wherein R, R₂ and R₄ are as defined above; and c) reacting a compound of Formula (VI) with a compound of Formula VII ##STR6## wherein R_(a) is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl group all of which may be optionally substituted; and R_(b) is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl group all of which may be optionally substituted; to yield a compound of Formula (VIII) ##STR7## wherein R_(b) is as defined above for Formula (VII), R is as defined above, and R₂ and R₄ are defined as for Formula (I);

d) reacting a compound of Formula (VEII) with a compound of Formula (IX) ##STR8## wherein Z is N(R^(d))₂, SR^(e), OR^(e), or R^(d).

R^(d) is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl;

R^(e) is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl; and

Y is, O, S, or NH;

to yield a compound of Formula (H), or a pharmaceutically acceptable salt thereof

Another aspect of the present invention are the novel compounds of Formula (VI), and (VIII) as defined herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel synthesis of a group of imidazole compounds, whose general structure is shown above in Formula (I) above, and further as described in Adams et al., WO 95/02591;Adams et al., WO 96/21452, published Jul. 18, 1996;Adams et al., WO 96/21654, published Jul. 18, 1996;and Adams et al., Attorney Docket No. P50347-2, U.S. Pat. No. 5,658,903 whose disclosures are all incorporated herein by reference.

Preferred compounds of Formula (I) have the structure: ##STR9## wherein R₁ is pyrimidin-4-yl which ring is optionally substituted with one or two substituents each of which is independently selected from optionally substituted C₁₋₁₀ alkyl, optionally substituted aryl, halogen, hydroxyl, thiol, C₁₋₁₀ alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylsulfinyl, CH₂ OR₁₂, amino, mono or di-C₁₋₁₀ alkyl substituted amino, NHR₂₁, N(R₁₀)C(O)R_(a) or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR₁₅ ;

R₄ is an optionally substituted phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl ring;

m is 0, or the integer 1 or 2;

m' is an integer having a value of 1 or 2,

m" is 0, or an integer having a value of 1 to 5;

R₂ is -(CR₁₀ R₂₀)_(n') OR₉, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀ -alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroaryl-C₁₋₁₀ -alkyl, (CR₁₀ R₂₀)_(n) OR₁₁, (CR₁₀ R₂₀)_(n) S(O)_(m) R₁₈, (CR₁₀ R₂₀)_(n) NHS(O)₂ R₁₈, (CR₁₀ R₂₀)_(n) NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NO₂, (CR₁₀ R₂₀)_(n) CN, (CR₁₀ R₂₀)_(n') SO₂ R₁₈, (CR₁₀ R₂₀)_(n) S(O)_(m') NR₁₃ R₁₄, (CR₁₀ R₂₀) _(n) C(Z)R₁₁, (CR₁₀ R₂₀)_(n) OC(Z)R₁₁, (CR₁₀ R₂₀)_(n) C(Z)OR₁₁, (CR₁₀ R₂₀).sub._(n) C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) C(Z)NR₁₁ OR₉, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)R₁₁, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)R₁₁, (CR₁₀ R₂₀)_(n) C(═NOR₆)R₁₁, (CR₁₀ R₂₀)_(n) NR₁₀ C(═NR₁₉)NR₁₃ R₁₄ , (CR₁₀ R₂₀)_(n) OC(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or 4-(R₁₂)-5-(R₁₈ R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted;

n is an integer having a value of 1 to 10;

n' is 0, or an integer having a value of 1 to 10;

Z is oxygen or sulfur;

R_(a) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄ alkyl;

R₃ is heterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈ ;

R₆ is hydrogen, a pharmaceutically acceptable application, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aryl, or C₁₋₁₀ alkanoyl;

R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀ R₂₀)_(n) OR₁₁ (CR₁₀ R₂₀)_(n) S(O)_(m) R₁₈, (CR₁₀ R₂₀)_(n) NHS(O)₂ R₁₈, (CR₁₀ R₂₀)_(n) NR₁₃ R₁₄ ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;

R₉ is hydrogen, --C(Z)R₁₁ or optionally substituted C₁₋₁₀ alkyl, S(0)₂ R₁₈, optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl;

R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl;

R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀ alkyl, aryl, arylthio alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl;

R₁₂ is hydrogen or R₁₆ ;

R₁₃ and R₁₄ is each independently selected from hydrogen or optionally substituted C₁₋₄ alkyl, optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉ ;

R₁₅ is R₁₀ or C(Z)-C₁₋₄ alkyl;

R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇ cycloalyl;

R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C₁₋₁₀ alkyl, heteroaryl or heteroarylalkyl;

R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl; and

R₂₁ is alkyl, aryl, arylC₁₋₆ alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl, heteroaryl, heteroarylC₁₋₆ alkyl, wherein each of these moieties may be optionally substituted;

or a pharmaceutically acceptable salt thereof

Preferably, for compounds wherein R₄ is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, the rings are optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, --C(Z)NR₇ R₁₇, -C(Z)OR₁₆, --(CR₁₀ R₂₀)_(v) COR₁₂, --SR₅, --SOR₅, --OR₁₂, halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, --ZC (Z)R₁₂, --NR₁₀ C(Z)R₁₆, or --(CR₁₀ R₂₀)_(v) NR₁₀ R₂₀ and which, for other positions of substitution, is halogen, cyano, --C(Z)NR₁₃ R₁₄, --C(Z)OR₃, --(CR₁₀ R₂₀)_(m") COR₃, --S(O)_(m) --OR₃, halo-substituted-C₁₋₄ alkyl, -C₁₋₄ alkyl --(CR₁₀ R₂₀)_(m") NR₁₀ C(Z)R₃, --NR₁₀ S(O)_(m') R₈, --NR₁₀ S(O)_(m') NR₇ R₁₇, --ZC(Z)R₃ or --(CR₁₀ R₂₀)_(m") NR₁₃ R₁₄.

Suitably, wherein R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇ R₁₇, excluding the moieties --SR₅ being --SR₇ R₁₇ and --SOR₅ being --SOH.; v is 0, or an integer having a value of 1 or 2;and m" is 0, or an integer having a value of 1 to 5.

Suitably, wherein R₇ and R₁₇ are each independently selected from hydrogen or C₁₋₄ alkyl or R₇ and R₁₇ together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₁₅.

Suitably, R₁₅ is R₁₀ or C(Z)-C₁₋₄ alkyl, and R₁₀ and Z are as defined for Formula (I).

The compounds of Formula (I) may be used in association with the treatment of cytokine mediated diseases in a mammal, or for the veterinary treatment of mammals who are in need of inhibition of cytokine production.

Another embodiment of the present invention are the novel compounds of the Formula (VI) having the structure: ##STR10## wherein R is optionally substituted C₁₋₁₀ alkyl, optionally substituted aryl, halogen, hydroxyl, thiol, C₁₋₁₀ (alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylsulfinyl, CH₂ OR₁₂ amino, mono or di-C₁₋₆ alkyl substituted amino, NHR₂₁, N(R₁₀)C(O)R_(a) or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR₁₅ ;

R_(a) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄ alkyl;

R₄ is an optionally substituted phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl ring;

R₂ is -(CR₁₀ R₂₀)n'OR₉, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroaryl-C₁₋₁₀ alkyl, (CR₁₀ R₂₀)_(n) OR₁₁, (CR₁₀ R₂₀)_(n) S(O)_(m) R₁₈, (CR₁₀ R₂₀)_(n) NHS(O)₂ R₁₈, (CR₁₀ R₂₀)_(n) NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NO₂, (CR₁₀ R₂₀)_(n) CN, (CR₁₀ R₂₀)_(n) "SO₂ R₁₈ , (CR₁₀ R₂₀)_(n) S(O)_(m") NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) C(Z)R₁₁, (CR₁₀ R₂₀)_(n) OC(Z)R₁₁, (CR₁₀ R₂₀)_(n) C(Z)OR₁₁, (CR₁₀ R₂₀)_(n) C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) C(Z)NR₁₁ OR₉, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)R₁₁, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)R₁₁, (CR₁₀ R₂₀)_(n) C(=NOR₆)R₁₁ (CR₁₀ R₂₀)_(n) NR₁₀ C(═NR₁₉)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) OC(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or 4-(R₁₂)-5-(R₁₈ R₁₉)4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted;

n is an integer having a value of 1 to 10

n' is 0, or an integer having a value of 1 to 10;

m' is an integer having a value of 1 or 2,

Z is oxygen or sulfur;

R₉ is hydrogen, --C(Z)R₁₁ or optionally substituted C₁₋₁₀ alkyl, S(O)₂ R₁₈, optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl;

R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl;

R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl;

R₁₂ is hydrogen or R₁₆ ;

R₁₃ and R₁₄ is each independently selected from hydrogen or optionally substituted C₁₋₄ alkyl, optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉ ;

R₁₅ is R₁₀ or C(Z)-C₁₋₄ alkyl;

R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇ cycloalkyl;

R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C₁₋₁₀ alkyl, heteroaryl or heteroarylalkyl;

R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl; and

R₂₁ is alkyl, aryl, arylC₁₋₆ alkyl, heterocyclic, heterocyclyl¢C₁₋₆ alkyl, heteroaryl, heteroarylC₁₋₆ alkyl, wherein each of these moieties may be optionally substituted.

Yet another embodiment of the present invention are the novel compounds of Formula (VIII) having the structure: ##STR11## wherein R_(b) is alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, or heterocyclicalkyl, all of which may be optionally substituted;

R is optionally substituted alkyl, optionally substituted aryl, ₁₋₄ alkyl, halogen, hydroxyl, thiol, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsufinyl, CH₂ OR₁₂, amino, mono or di-C₁₋₆ alkyl substituted amino, NHR₂₁, N(R₁₀)C(O)R_(a) or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR₁₅ ;

R_(a) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄ alkyl;

R₄ is an optionally substituted phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl ring;

R₂ is -(CR₁₀ R₂₀)_(n') OR₉, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl₁₋₁₀ -alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroaryl-C₁₋₁₀ -alkyl, (CR₁₀ R₂₀)_(n) OR₁₁, (CR₁₀ R₂₀)_(n) S(O)_(m) R₁₈, (CR₁₀ R₂₀)_(n) NHS(O)₂ R₁₈, (CR₁₈ R₂₀)_(n) NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NO₂, (CR₁₀ R₂₀)_(n) CN, (CR₁₀ R₂₀)_(n") SO₂ R₁₈, (CR₁₀ R₂₀)_(n) S(O)_(m') NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) C(Z)R₁₁, (CR₁₀ R₂₀)_(n) OC(Z)R₁₁, (CR₁₀ R₂₀)_(n) C(Z)OR₁₁, (CR₁₀ R₂₀)_(n) C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) C(Z)NR₁₁ OR₉, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)R₁₁, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)NR,₁₃ R₁₄, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)R₁₁, (CR₁₀ R₂₀)_(n) C(═NOR₆)R₁₁, (CR₁₀ R₂₀)_(n) NR₁₀ C(═NR₁₉)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) OC(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or 4-(R₁₂)-5-(R₁₈ R₁₉)-4,5-dihydro- 1,2,4oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted;

n is an integer having a value of 1 to 10

n' is 0, or an integer having a value of 1 to 10;

m' is an integer having a value of 1 or 2,

Z is oxygen or sulfur;

R₉ is hydrogen, --C(Z)R₁₁ or optionally substituted C₁₋₁₀ alkyl, S(O)₂ R₁₈, optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl;

R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkl;

R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl;

R₁₂ is hydrogen or R₁₆ ;

R₁₃ and R₁₄ is each independently selected from hydrogen or optionally substituted C₁₋₄ alkyl, optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉ ;

R₁₅ is R₁₀ or C(Z)-C₁₋₄ alkyl;

R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇ cycloalkyl;

R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C₁₋₁₀ alkyl, heteroaryl or heteroarylalkyl;

R₁₉ is hydrogen, cyano, C₁₋₄ alkl, C₃₋₇ cycloalkyl or aryl;

R₂₁ is C₁₋₆ alkyl, aryl, arylC₁₋₆ alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl, heteroaryl, heteroarylC₁₋₆ alkyl, wherein each of these moieties may be optionally.

Unless otherwise defined in any of the references incorporated herein, the term "optionally substituted" as used herein shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted C₁₋₁₀ alkyl;C₁₋₁₀ alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1 or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl; amino, mono & di-substituted amino, such as in the NR₇ R₁₇ group; or where the R₇ R₁₇ may together with the nitrogen to which they are attached cyclized to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S; C₁₋₁₀ alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted C₁₋₁₀ alkyl, such CF₂ CF₂ H, or CF₃ ;an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenylethyl, wherein these aryl moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; C₁₋₁₀ alkoxy; S(O)_(m) alkyl; amino, mono & di-substituted amino, such as in the NR₇ R₁₇ group; alkyl, or CF₃.

A general method of synthesis for compounds of Formula (I) is shown below Scheme 1. ##STR12##

The synthesis provided for in these Schemes is applicable for the producing compounds of Formula (I) having a variety of different R₁, R₂, and R₄ groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the imidazole nucleus has been established, further compounds of Formula (I) may be prepared by applying standard techniques for functional group interconversion, well known in the art. For instance, on the pyrimidine ring, halogen from OH, by reacting with POX₃ or PX₃, wherein X is halogen; C₁₋₄ alkylsulfinyl from C₁₋₄ alkylthio by oxidation of the sulfur with an appropriate oxidant; N(R₁₀)C(O)R_(a) from NH(R₁₀) by acylation on nitrogen with an appropriate acylating agent; YC(O)R_(a) where Y is any leaving group. For other alternative groups on the R₂ or R₄ moiety, such as --C(O)NR₁₃ R₁₄ from -CO₂ CH₃ by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR₁₃ R₁₄ in CH₃ OH; --OC(O)R₃ from --OH with e.g., CIC(O)R₃ in pyridine; --NR₁₀ -C(S)NR₁₃ R₁₄ from --NHR₁₀ with an alkylisothiocyante or thiocyanic acid; NR₆ C(O)OR₆ from --NHR₆ with the alkyl chloroformate; ---NR₁₀ C(O)NR₁₃ R₁₄ from --NHR₁₀ by treatment with an isocyanate, e.g. HN═C═O or R₁₀ N═C═O; --NR₁₀ --C(O)R₈ from --NHR₁₀ by treatment with Cl--C(O)R₃ in pyridine; --C(═NR₁₀)NR₁₃ R₁₃ R₁₄ from --C(NR₁₃ R₁₄)SR₃ with H₃ NR₃ ⁺ OAc⁻ by heating in alcohol; --C(NR₁₃ R₁ )SRE3 from --C(S)NR₁₃ R₁₄ with R₆ -I in an inert solvent, e.g. acetone; --C(S)NR₁₃ R₁₄ (where R₁₃ or R₁₄ is not hydrogen) from --C(S)NH₂ with HNR₁₃ R₁₄ --C(═NCN)--NR₁₃ R₁₄ from --C(═NR₁₃ R₁₄) --SR₃ with NH₂ CN by heating in anhydrous alcohol, alternatively from --C(═NH)--NR₁₃ R₁₄ by treatment with BrCN and NaOEt in EtOH; --NR₁₀ --C(═NCN)SR₈ from --NHR₁₀ by treatment with (R₈ S)₂ C═NCN; --NR₁₀ SO₂ R₃ from --NHR₁₀ by treatment with ClSO₂ R₃ by heating in pyridine; --NR₁₀ C(S)R₃ from --NR₁₀ C(O)R₈ by treatment with Lawesson's reagent 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide!; --NR₁₀ SO₂ CF₃ from --NHR₆ with triflic anhydride and base wherein R₃, R₆, R₁₀, R₁₃ and R₁₄ are as defined in Formula (I) herein.

Precursors of the groups R₁, R₂ and R₄ can be other R₁, R₂ and R₄ groups which can be interconverted by applying standard techniques for functional group interconversion. For example a compound of the formula (I) wherein R₂ is halo-substituted C₁₋₁₀ alkyl can be converted to the corresponding C₁₋₁₀ alkyl₃ derivative by reacting with a suitable azide salt, and thereafter if desired can be reduced to the corresponding C₁₋₁₀ alkyl NH₂ compound, which in turn can be reacted with R₁₈ S(O)₂ X wherein X is halo (e.g., chloro) to yield the corresponding C₁₋₁₀ alkylNHS(O)₂ R₁₈ compound.

Alternatively a compound of the formula (I) wherein R₂ is halo-substituted C₁₋₁₀ -alkyl can be reacted with an amine R₁₃ R₁₄ NH to yield the corresponding C₁₋₁₀ --alkylNR₁₃ R₁₄ compound, or can be reacted with an alkali metal salt of R₁₈ SH to yield the corresponding C₁₋₁₀ alkylSR₁₈ compound.

In Scheme I the compounds of Formula (I) are suitably prepared by reacting a compound of the Formula (II) with a compound of the Formula (III) wherein R is any suitable group, such as H, alkyl, substituted alkyl, aryl, aryl alkyl, heterocyclic, heterocylic alkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or amino, and R₂ is as defined herein, for Formula (I), or is a precursor of the group R₂, and thereafter if necessary converting a precursor of R₂ to the desired R₂ group. Suitable precursor groups of R₂ include various well known protecting groups, particularly when R₂ is a nitrogen containing heterocyclic ring, such as piperidine. Suitable protecting groups are described in many references, for instance, Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981. When R₂ is an optionally substituted cycloakyl, such as a 4-hydroxy-cyclohexyl, the precursor cyclohexanone could be used, and then reduced to the alcohol.

The compounds of Formula (IV) which are formed are either isolated, or more suitably reacted in situ with compounds of the Formula (V) and a suitable base, where Ar is an optionally substituted phenyl group and R₄ is defined herein, for compounds of Formula (I), to produce compounds of the Formula (VI). Heating compounds of the Formula (VI) with an enaminating reagent such as a compound of Formula (VII), or derivatives thereof, such as reagents of similar structure and reactivity to DMFDMA which include tris(dimethylamino)methane or tert-butoxybis(dimethylamino)-methane, or any other reactive species known to behave as enaminating agents; which produces compounds of the Formula (VI), which can be isolated, or more preferably reacted in situ with reagents of Formula (IX), where Y and Z are defined for Formula (IX) above to produce the compounds of Formula (I).

An alternative to using reagents of Formula (VII) to produce an enamine of Formula (VIII) is to react compounds of Formula (VI) with formylating agents, such as formate esters, or formamides, to produce 1,3-dicarbonyl compounds which, when in their tautomeric form, are similar to compounds of the Formula (VIII), where (R_(b))₂ N═OR, wherein R is alkyl, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocylic, heterocyclicalkyl, or silyl. Compounds of the Formula (VIII), where (R_(b))₂ N═OR can be reacted directly with reagents of the Formula (IX) to produce compounds of the Formula (I).

The process is exemplified, in Scheme I, by reaction of pyruvaldehyde (Formula II, R═H), which is typically obtained as an aqueous solution, with a primary amine (Formula III) in a solvent to produce imines of the Formula (IV), employing a modification of the method of van Koten (see van der Poel and van Koten, Synth. Commun. 1978, 8, 305 whose disclosure is incorporated by reference herein in its entirety). Suitable solvents for this process include, but are not limited to, ethereal solvents, such as tetrahydrofuran (THF), t-butyl methyl ether TBME), diethyl ether, acetonitrile (MeCN), ethyl acetate (EtOAc), N,N,-dimethylformamide (DMF), and dimethylsulfoxide (DMSO). The reaction requires times of ˜1 min to about 24 h, with the preferred times being from about 10-20 min. The reaction is suitably conducted at temperatures ranging from about 0° C. to room temperature, or may be performed at elevated temperatures, of at least 100° C., if so desired.

Imines of Formula (IV) can be dissolved in a solvent and reacted with compounds of Formula (V), with or without added base, to produce compounds of Formula (VI). A suitable base for this reaction is potassium carbonate, or those noted below and suitable solvents include DMF and DMSO as noted below. The reaction can be conducted at 0 ° C., room temperature or as high as about 65° C.

A further embodiment of the present invention involves the preparation of the imines of the Formula (IV) in situ, followed by reaction with isonitriles of the Formula (V) to produce imidazoles of the Formula (VI). In this process, aldehydes of Formula (II) are combined with primary amines of Formula (III) in a suitable solvent, and after the prescribed amount of time the imine formation is considered complete and isonitriles of the Formula (V) and a suitable base are added. Suitable solvents include, but are not limited to, acetonitrile, THF, MeCN, toluene, EtOAc, DMF, and DMSO and mixtures thereof. The imine formation requires times of ˜5 min to about 6 hours, with the preferred times being about 10-20 min and can be conducted at temperatures ranging from about 0° C. to 60° C. After addition of the isonitrile, the reaction typically requires an additional 2 to 24 hours at temperatures of 0° C. to 65° C. to go to completion. The reaction proceeds without bases or in the presence of suitable bases, including but not limited to including inorganic and organic amine bases, such as potassium carbonate, sodium carbonate, K₃ PO₄, K₂ HPO₄, Na₂ HPO₄, including inorganic and organic amine bases, such as secondary amines, e.g. morpholine, pyrrolidine, piperidine, and tertiary amines, such as DBU or DBM, as well as tetraethyl guanidine.

Imidazoles of the Formula (VI) can be converted to compounds of the Formula (VIII) by the action of agents of the Formula (VII), or agents of similar structure and reactivity. The process involves heating compounds of Formula (VI) with N,N-dimethylformamide dimethyl acetal (DMFDMA) with no solvent, or a suitable solvent, at temperatures higher than about 70° C. Suitable solvents include, but are not limited to toluene, ethanol, 1-propanol, 2-propanol, DMF, and DMSO. Reagents of similar structure and reactivity to DMFDMA include tris(dimethylamino)methane or tert-butoxybis(dimethylamino)methane, or other reactive species know to behave as enaminating agents. With some of the more reactive enaminating reagents, the temperature for this process can be lower than the 70° C. mentioned above.

Compounds of the Formula (VIII) can be isolated, or prepared in situ, and reacted further as shown in Scheme 1. In either case, the reaction involves reacting compounds of Formula (VIII) with compounds of Formula (IX) in a suitable solvent, and a suitable base, if necessary. Suitable solvents include, but are not limited to, alcohols, such as methanol, ethanol, 1-propanol and 2-propanol, toluene, alone or in combination with an alcohol, DMF, DMSO, or combinations of the above. Reagents of the Formula (IX), when Y is NH, are typically obtained as an acid salt, and as such, require the action of a base to react with compounds of the Formula (VIII). When Y is O or S, the reaction may require either acid or base catalysis. Suitable bases include, but are not limited to, NaOMe, NaOEt, potassium carbonate, and KOH. Temperatures of about 25 to about 110° C. have been found to be useful for this conversion, with temperatures>65° C. being preferred.

A further embodiment of the present invention involves the preparation of imidazoles of the Formula (I) as shown in Scheme 1 in a single pot. The reaction conditions mentioned above are generally suitable for conducting the synthesis in one pot, with one modification. The conversion of compounds of the Formula (VI) to compounds of the Formula (VIII) requires anhydrous conditions. Water is introduced into the reaction when using pyruvaldehyde (II, R═H) as it is sold as a solution in water, which must be removed before proceeding. Following complete conversion of (IV) and (V) to form (VI), suitable methods of dehydration include, but are not limited to the following: using excess DMFDMA (˜10 equivalents) to both react with water and then with ketones (VI); azeotropically removing water with cosolvents such as toluene, or alcohols; adding other drying agents such as MgSO4;or triethyl orthoformate.

SYNTHETIC EXAMPLES

The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon atmosphere unless otherwise indicated.

In the Examples, all temperatures are in degrees Centigrade (° C.). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. ¹ H-NMR (hereinafter "NMR") spectra were recorded at 300 MHz using a Bruker AM 300 spectrometer. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant. Flash chromatography is generally run over Merck Silica gel 60 (230-400 mesh).

EXAMPLE 1 Ethyl 4-(2-oxopropylidene)amino-1-piperidinecarboxylate ##STR13##

To a solution of pyruvaldehyde (40% w/w solution in water, 2.67 mL, 3.15 g, 17.5 mol) in 50 ml of Et₂ O at room temperature was added dropwise ethyl 4-aminopiperidecarboxylate (3.0 mL, 3.01 g, 17.5 mmol). After 20 min, the solution was diluted with 50 mL of Et₂ O and washed with 3×30 mL of water. The solution was concentrated in vacuo to yield 2.3 g (58%) of the imine product which was used as such in the subsequent step: ¹ H NMR (CDCl₃) δ7.58 (1H, s), 4.07 (2H, q, J=7.1 Hz)), 4.04 (2H, m), 3.39 (1H, m), 3.02 (2H, m), 2.31 (3H, s), 1.65 (4H, m), 1.19 (3H, t, J=7.1 Hz).

Example (Ia): Alternative conditions utilized in above noted synthesis include MeCN as solvent and mixing the reagents at 0° C.

EXAMPLE 2 1 -(1-Ethoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-acetylimidazole: ##STR14##

To a solution of the imine described in Example 1 above (1.12 g, 4.95 mmol) in 9 mL of DMF at room temperature was added α-(p-toluenesulfonyl)-4 -fluorobenzylisonitile (1.30 g, 4.50 mmol) and K₂ CO₃ (0.68 g, 4.95 mmol). After 22 h, the solution was diluted with 75 mL of EtOAc and washed with 2×60 mL of 3N HCl. The aqueous layers were combined and basified with excess solid K₂ CO₃ until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2×75 mL of EtOAc. The combined organics were washed with 3×50 mL of water and concentrated in vacuo. The residue was recrystallized from CHCl₃ /Hexane to yield the imidazole product (1.05 g, 65%) which was used in subsequent steps: mp=118-19 ° C.; IR (KBr) 1691, 1681, 1640 cm⁻¹.,¹ H NMR (CDCI₃) δ7.74 (1H,s), 7.44 (2H, m), 7.14 (2H, t, J=8.6 Hz), 5.00 (1H, tt, J=3.7, 12.1Hz), 4.35 (2H, m), 4.17 (2H, q, J=7.1 Hz), 2.93 (2H, m), 2.18 (2H, br d, J=12.9 Hz), 2.12 (3H, s), 1.80 (2H, dq, J=4.2, 12.4 Hz), 1.28 (3H, t, J=7.1 Hz); ¹³ C NMR (CDCL₃) d 191.00, 164.74, 161.45, 155.31, 149.77, 137.39, 131.46, 131.35, 126.99, 115.63, 115.34, 61.59, 54.85, 43.29, 33.40, 30.45, 14.63; ¹³ C NMR (CDCl₃) δ191.00, 164.75, 161.45, 155.31, 149.77, 137.39, 131.46, 131.35, 126.99, 115.63, 115.35, 61.59, 54.85, 43.29, 33.40,30.45, 14.63; Anal. Calcd for C₁₉ H₂₂ N₃ O₃ F: C, 63.5; H; 6.2; N, 11.7. Found C, 63.1; H, 63.1; H, 6.1; N, 11.5.

In an alternative procedure to that listed above, the title compound was prepared in the following manner: To a solution of pyruvaldehyde (40% w/w solution in water, 3.97 mL, 4.68 g, 25.94 mmol) in 34 mL of DMSO at room temperature was added dropwise ethyl 4-ano-piperidinecarboxylate (4.45 mL, 4.47 g, 25.94 mmol). After 10 min α-(p-toluenesulfonyl)-4-fluoro-benzylisonitrile (5.0 g, 17.3 mmol) and K₂ CO₃ (2.39 g, 17.3 mmol) were added. After 15 h, the solution was diluted with 100 mL of EtOAc and washed with 2×10 mL of 3N HCl. The aqueous layers were combined and basified with excess solid K₂ CO₃ until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2×150 mL of EtOAc. The combined organics were washed with 3×75 ml of water and concentrated in vacuo to yield the imidazole product (4.65 g, 75%) which was used as is in subsequent steps.

Alternative conditions for this synthesis include the Examples shown below:

    __________________________________________________________________________                    Temp for imine                            Temp for                                    Imine     Solvent Base/eq                    formation                            cycloaddition                                    formation time     __________________________________________________________________________     DMF     K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    15 min     DMF     K.sub.2 CO.sub.3 /1.1                    room temp.                            room temp.                                    15 min     DMF     K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    20 min     DMF     K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    17 min.     DMF     K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    80 min     DMF     K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    75 min     DMF     K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    6 h     DMF     K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    2 h     DMF     K.sub.2 CO.sub.3 /1.1                    room temp.                            room temp.                                    85 min     DMF     K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    12 min     DMF     K.sub.2 CO.sub.3 /1.2                    45° C.                            45° C.                                    12 min     DMF     K.sub.2 CO.sub.3 /1.2                    60° C.                            60° C.                                    14 min     DMF/MgSO.sub.4             K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    12 min     DMF     K.sub.2 CO.sub.3 /1.2                    room temp. to 40                            room temp.                                    12 min                    ° C., distill     DMF     K.sub.2 CO.sub.3 /1.1                    40° C.                            40° C.                                    10 min.     DMF     K.sub.2 CO.sub.3 /1.25                    0° C.                            room temp.                                    4 h     DMF     K.sub.2 CO.sub.3 /1.2                    0° C.                            0° C.                                    2.33 h     DMF     NaHCO.sub.3 /1.3                    room temp.                            room temp.                                    75 min.     MeCN    K.sub.2 CO.sub.3 /1.25                    room temp.                            room temp.                                    25 min.     MeCN    K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    5 min.     MeCN    K.sub.2 CO.sub.3 /1.2                    room temp.                            room temp.                                    10 min.     MeCN    K.sub.2 CO.sub.3 /1.25                    0° C.                            room temp.                                    15 min.     MeCN    K.sub.2 CO.sub.3 /1.2                    0° C.                            0° C.                                    145 min.     DMSO    K.sub.2 CO.sub.3 /1.25                    room temp.                            room temp.                                    15 min.     THF     morpholine/3                    room temp.                            room temp.                                    1 h     THF     K.sub.2 CO.sub.3 /1.2                    0° C.                            0° C.                                    145 min.     Toluene K.sub.2 CO.sub.3 /1.25                    room temp.                            room temp.                                    15 min.     EtOAc   K.sub.2 CO.sub.3 /1.0                    room temp.                            room temp.                                    11 min.     __________________________________________________________________________

EXAMPLE 3 1-(1-Ethoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(3-N,N-dimethylano-trans-1-propenone) imidazole ##STR15##

The ketoimidazole prepared in Example 2 above (0.4 g, 1.11 mmol) was dissolved in 4 mL of DMSO and N,N-dimethylformamide dimethyl acetal (0.18 mL, 0.16 g, 1.33 mmol) and was heated at 90° C. for 5.5 h. The solution was cooled to room temperature and the solvents were removed under vacuum by Kugel-Rohr distillation. The residue was purified by preparative TLC using hexanes/ethyl acetate (1:1) and eluting twice to give 0.3 g (65%) of the title compound as a brown solid: ¹ H NMR (CDCl₃) δ7.65 (1H, s), 7.55 (2H, m), 7.48 (1H, m), 7.02 (2H, t, J=8.7 Hz), 5.02 (1H, d, J=12.6 Hz), 4.91 (1H, m), 4.30 (2H, m), 4.13 (2H, q, J=7.1 Hz), 2.99 (3H, br s), 2.89 (2H, m), 2.51 (3H, br s), 2.18 (2H, d, J=12.1 Hz), 1.78 (2H, dq, J=4.3, 12.3 Hz), 1.26 (3H, t, J=7.1 Hz).

EXAMPLE 4 1-(1 -Ethoxycarbonyl-4-piperidinyl)4-(4-fluorophenyl)-5-{2-(methylamino)-4-pyrimidinyl) imidazole: ##STR16##

To a solution of the ketoimidazole prepared in Example 2 above (2.1 g,5.85 mmol) in 10.5 mL of 1-propanol was added N,N-dimethylformamide dimethyl acetal (1.32 mL, 1.18 g, 9.94 mmol) and the solution was heated at 100° C. for 6 h. At this time, TLC indicated no starting material and N-methylguanidine•HCl (0.96 g, 8.77 mmol) and NaOEt (21% w/w solution, 3.50 mL, 3.05 g, 9.35 mmol) were added. After 18 hours, the solution was cooled to room temperature, diluted with 40 mL of water, 50 mL of 3N HCl and 50 mL of EtOAC. The layers were separated and the organic layer wash washed again with 20 mL of 3N HCl. The combined aqueous layers were basified with solid K₂ CO₃ until bubbling ceased. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organics were washed with 3×100 mL of water, concentrated and the residue was recrystallized from EtOAc to give 1.24 g (50%) of the title compound: mp=205-206° C.; IR (KBr) 3242, 3110, 1695, 1588, 1568, 1532, 1507 cm⁻¹ ; ¹ H NMR (CDCl₃) δ8.15 (1H, d, J=5.0 Hz), 7.71 (1H, s), 7.44 (2H, m), 6.97 (2H, t, J=8.7 Hz), 6.40 (1H, d, J=5.0 Hz), 5.18 (1H, m), 4.83 (1H, m), 4.34 (2H, m),4.15 (2H, q, J=7.1 Hz), 3.02 (3H, d, J=5.0 Hz), 2.81 (2H, m), 2.19 (2H, m), 1.87 (2H, dq, J=4.4, 12.5 Hz), 1.27 (3H, t, J=7.1 Hz); ¹³ C NMR (CDCl₃) δ164.00, 163.03, 160.73, 158.51, 158.32, 155.31, 141.96, 135.57, 130.52, 130.07, 129.97, 125.01, 115.39, 115.11, 111.73, 61.61, 53.80, 43.42, 33.43, 28.43, 14.63; Anal. Cald for C₂₂ H₂₅ N₆ O₂ F; C, 62.2; H, 5.9; N, 19.8; Found C, 61.9, H, 6.0; N, 19.4.

Examples 4 (a) and (b) include the alternative conditions

    ______________________________________     Solvent DMFDMA temp   Base    Pyrimidine temp.     ______________________________________     EtOH     85° C.                           NaOMe   85 ° C.     DMF     100° C.                           NaOMe   65 ° C.     ______________________________________

EXAMPLE 5 1-(1-Ethoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-(amino)-4-pyrimdinyl)imidazole: ##STR17##

To a solution of the ketoimidazole prepared in Example 2 above (2.6 g, 7.24 mmol) in 15 mL of DMF was added N,N-dimethylformamide dimethyl acetal (1.92 mL, 1.72 g, 14.5 mmol) and the solution was heated at 120° C. for 2 h. At this time, TLC and HPLC indicated no starting material and the solution was cooled to 95° C. and ethanol (30 mL), guanidine•HCl (2.77 g, 28.95 mmol) and K₂ CO₃ (4.0 g, 28.9 mmol) were added. After 16 hours, HPLC indicated that the reaction was complete and the solution was cooled to room temperature. The solution was diluted with 100 mL of EtOAc and washed with 2×150 mL of 3N HCl. The aqueous layers were combined and basified with excess solid K₂ CO₃ until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2×150 mL of EtOAc. The combined organics were dried over Na₂ SO₄ and activated charcoal, filtered through Celite, and concentrated in vacuo. The residue was recrystallized from EtOAc/MeOH/Hexanes to yield the imidazole product (0.9 g, 30%) as a beige solid: mp=228-230° C.; IR (KBr) 3321, 3157, 1712, 1658, 1568, 1507, 1470, 1437 cm⁻¹ ; ¹ H NMR (CDCl₃) δ8.17 (1H, d, J=5.3 Hz), 7.71 (1H, s), 7.43 (2H, m), 7.00 (2H, t, J=8.7 Hz), 6.50 (1H, d, J=5.3 Hz), 5.16 (2H, br s), 4.74 (1H, tt, J=3.7, 12.0 Hz), 4.35 (2H, m), 4.15 (2H, q, J=7.1 Hz), 2.82 (2H, t, J=12.5 Hz), 2.15 (2H, d, J=12.5 Hz), 1.85 (2H, m), 1.28 (3H, t, J=7.1 Hz); ¹³ C NMR (DMSO-d₆) δ163.61, 162.76, 159.54, 158.66, 158.01, 154.35, 138.88, 136.25, 131.00, 129.16, 129.05, 124.98, 115.08, 114.80, 110.84, 60.64, 53.06, 42.70, 32.48, 14.43; Anal. Calcd for C₂₁ H₂₃ N₆ O₂ F; C, 61.4; H, 5.7; N, 20.5; Found C, 61.0, H, 5.5; N, 20.3.

Examples 5 (a) to (d) include the alternative conditions

    ______________________________________     Solvent            DMFDMA temp  Base         Pyrimidine temp.     ______________________________________     EtOH    90 ° C.                         NaOMe        80° C.     EtOH    90 ° C.                         NaOMe        85° C.     DMF    120 ° C.                         K.sub.2 CO.sub.3 /EtOH                                      95° C.     Toluene            115 ° C.                         K.sub.2 CO.sub.3 /EtOH/IPA                                      80-90 ° C.     ______________________________________

EXAMPLE 6 1-(4-piperidinyl)-4-(4-fluorophenyl)-5- 2-(amino)-4-pyrimdinyl!imidazole ##STR18##

To a solution of the ketoimidazole prepared in Example 2 above (1.4 g, 3.89 mmol) in 5 mL of toluene was added N,N-dimethylformamide dimethyl acetal (1.04 mL, 0.93 g, 7.80 mmol) and the solution was heated at 115° C. for 4 h. At this time, TLC and HPLC indicated no starting material and the solution was cooled to 80 ° C. and 2-propanol (25 mL), guanidine•HCl (1.49 g, 15.6 mmol) and K₂ CO₃ (2.15 g, 15.6 mmol) were added. After 16.5 hours, HPLC indicated that the reaction was 60% complete. Ethanol (20 mL) was added and heating was continued at 90° C. for 24 h, at which point HPLC showed none of the aminoenone remaining. AT this point, KOH (2.19 g, 38.9 mmol) and water (10 mL) were added and heating was continued at 95° C. for 8 h. An additional poriton of KOH (2.2 g, 38.9 mmol) was added. After 15 h of heating an additional 4.4 g of KOH was added and heated for 48 h. The solution was cooled to room temperature, diluted with 20 mL of water and the solid which formed was filtered, washed with water (50 mL) and Et₂ O (50 mL), and dried to yield 0.44 g (34%) of the title compound as a beige solid: mp=199-200° C.; IR (KBr) 3471, 3395, 3314, 3167, 1635, 1576, 1566, 1507, 1460 cm⁻¹ ; ¹ H NMR (DMSO-d₆) δ 8.20 (1H, d, J=5.0 Hz), 7.98 (1H, s), 7.43 (2H, m), 7.12 (2H, t, J=8.9 Hz), 6.81 (2H, br s), 6.41 (1H, d, J=5.0 Hz), 4.31 (1H, m), 2.97 (2H, d, J=12.4 Hz), 2.45 (2H, m), 1.86 (2H, m), 1.74 (2H, dq, J=3.7, 11.8 Hz); ¹³ C NMR (DMSO-d₆) δ163.67, 162.70, 159.47, 158.68, 158.33, 138.64, 135.79, 130.98, 128.98, 128.88, 125.05, 115.05, 114.77, 110.96, 53.84, 45.39, 34.08; Anal. Calcd for C₁₈ H₁₉ N₆ F•0.5 H₂ O: C, 62.2; H, 5.8; N, 24.2. Found C, 61.9; H, 5.7; N, 23.9.

In an alternative procedure, the substrate was dissolved in 1-PrOH and heated at about 95° C. with DMFDMA, then heated with guanidine•HCl and K₂ CO₃ at 95° C. and when the pyridine formation was completed, the reaction was heated with excess KOH until product formation was complete.

EXAMPLE 7 2,2,6,6-Tetramethyl-4-(2-oxopropylidene)aminopiperidine ##STR19##

To a solution of pyruvaldehyde (40% w/w solution in water, 2.68 mL, 3.16 g, 17.5 mol) in 30 ml of TBME at room temperature was added dropwise 2,2,6,6-tetramethyl-4-amino-piperidine (2.0 mL, 2.19 g, 14.0 mmol). After 30 min, the solution was diluted with 50 mL of TBME and washed with 3×25 mL of water and 25 mL of brine. The solution was concentrated in vacuo to yield 2.1 g (71%) of the imine product which was used as such in the subsequent step: ¹ H NMR (CDCl₃) δ7.64 (1H, s), 3.70 (1H, tt, J=3.9, 11.6 Hz), 2.34 (3H, s), 1.61 (2H, dd, J=3.9, 13.0 Hz), 1.32 (2H, t, J=12.2 Hz), 1.21 (6H, s), 1.14 (6H, s).

EXAMPLE 8 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5-acetylimidazole: ##STR20##

a solution of pyruvaldehyde (40% w/w solution in water, 7.56 mL, 8.91 g, 49.5 mmol) in 90 mL of DMSO at room temperature was added dropwise 2,2,6,6-tetramethyl-4-amino-piperidine (9.24 mL, 8.43 g, 65.4 mmol). After 10 min α-(p-toluenesulfonyl)-4-fluorobenzylisonitile (13.0 g, 44.95 mmol) and K₂ CO₃ (7.46 g, 53.95 mmol) were added. After 23 h, the solution was diluted with 250 mL of EtOAc and washed with 2×200 mL of 3N HCl. The aqueous layers were combined and basified with excess solid K₂ CO₃ until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2×250 mL of EtOAc. The combined organics were washed with 3×100 mL of water and concentrated in vacuo to yield the title compound (11.6 g, 75%) as a brown oil, which could be recrystallized from CHCl₃ /hexanes: mp=134-36° C.; IR (KBR) 3430, 3144, 1659, 1653, 1219 cm⁻¹ ; ¹ H NMR (CDCl₃) δ7.76 (1H, s), 7.43 (2H, m), 7.12 (2H, t, J=8.7 Hz), 5.39 (1H, tt, J=3.1, 12.5 Hz), 2.11 (3H, s), 2.10 (2H, m), 1.50 (2H, t, J=12.2 Hz), 1.37 (6H, s), 1.22 (6H, s); ¹³ C NMR (CDCl₃) δ190.77, 164.69, 161.41, 149.79, 137.42, 131.47, 131.36, 127.03, 115.57, 115.29, 52.02, 50.57, 46.20, 34.61, 30.45, 28.06.

Alternative reaction conditions for this synthesis included

    __________________________________________________________________________                     Imine                     formation                             Cycloaddition                                    Imine     Solvent Base eq.                     temp    temp.  formation time     __________________________________________________________________________     DMF     K.sub.2 CO.sub.3 /1.25                     room temp.                             room temp.                                    15 min.     DMF/toluene             K.sub.2 CO.sub.3 /1.15                     room temp to                             room temp.                                    80 min.                     65° C. (-H.sub.2 O)     DMF     none    room temp.                             room temp.                                    15 min.     DMF/EtOAc             K.sub.2 CO.sub.3 /1.2                     room temp.                             room temp.                                    15 min.     DMSO    K.sub.2 CO.sub.3 /1.25                     room temp.                             room temp.                                    20 min.     DMSO/toluene             K.sub.2 CO.sub.3 /1.15                     room temp to                             room temp.                                    35 min.                     55° C. (--H.sub.2 O)     DMSO/   K.sub.2 CO.sub.3 /1.2                     room temp to                             room temp.                                    40 min.     (MeO).sub.3 CH  55° C. (--H.sub.2 O)     DMSO    morpholine/1.3                     room temp.                             room temp.                                    15 min.     DMSO    pyrrolidine/1.3                     room temp.                             room temp.                                    15 min.     DMSO    K.sub.3 PO.sub.4 /1.5                     room temp.                             room temp.                                    15 min.     DMSO    K.sub.2 HPO.sub.4 /1.5                     room temp.                             room temp.                                    15 min.     DMSO    DBU/1.1 room temp.                             room temp.                                    15 min.     DMSO    Na.sub.2 CO.sub.3 /1.2                     room temp.                             room temp.                                    15 min.     DMSO    Na.sub.2 HPO.sub.4 /1.5                     room temp.                             room temp.                                    15 min.     DMSO    K.sub.2 HPO.sub.4 /3.0                     room temp.                             room temp.                                    15 min.     DMSO    morpholine/1.05                     room temp.                             room temp.                                    18 min.     DMSO    morpholine/1.0                     room temp.                             room temp.                                    10 min.     EtOAc   morpholine/1.0                     room temp.                             room temp.                                    10 min.     EtOAc   K.sub.2 CO.sub.3 /1.0                     room temp                             room temp.                                    12 min.     EtOAc   K.sub.2 CO.sub.3 /1.0                     room temp                             50° C.                                    13 min.     EtOAc   K.sub.2 CO.sub.3 /1.0                     room temp                             35° C.                                    15 min.     EtOAc   K.sub.2 CO.sub.3 /1.0                     room temp                             40° C.                                    15 min.     __________________________________________________________________________

EXAMPLE 9 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(3-N,N-dimethylamino-trans-1-propenone)imidazole ##STR21##

The ketoimidazole prepared in Example 8 above (0.75 g, 2.18 mmol) was dissolved in 10 mL of toluene and N,N-dimethylformamide diethyl acetal (0.43 mL, 0.39 g, 3.28 mmol) and was heated at 115° C. for 20 h. The solution was cooled to room temperature and the solvents were removed under vacuum. The residue was passed through a short plug of silica gel and eluted with EtOAc/MeOH (1:1), and concentrated to give the title compound (0.65 g 76%) of the title compound as a brown solid: ¹ H NMR (CDCl₃) δ7.65 (1H, s), 7.56 (2H, m), 7.46 (1H, d, J=12.2 Hz), 7.01 (2H, t, J=8.8 Hz), 5.32 (1H, m), 5.01 (1H, d, J=12.6 Hz), 2.96 (3H, br s), 2.48 (3H, br s), 2.09 (2H, dd, J=3.1, 12.0 Hz), 1.44 (2H, t, J=12.3 Hz 1.31 (6H, s), 1.17 (6H, s).

EXAMPLE 10 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5- 2-(methylamino)-4-pyrimidinyl!imidazole ##STR22##

To a solution of the ketoimidazole prepared in Example 8 above (8.0 g, 23.3 mmol) in 100 mL of DMSO was added N,N-dimethylformamide dimethyl acetal (6.19 mL, 5.55 g, 46.6 mol) and the solution was heated at 100° C. for 16 h. At this time, HPLC indicated no starting material and guandine•HCl (4.45 g, 46.6 mmol) and K₂ CO₃ (6.44 g, 46.6 mmol) were added and heating was continued at 100° C. After 9 hours, the solution was cooled to room temperature, diluted with 100 mL of water, DMSO and MeOH, and filtered. The filtrate was diluted with 200 mL of EtOAc and 400 mL of water. The layers were separated and the aqueous layer was extracted 3×200 mL of EtOAc. The organic layers were combined and washed with 3×100 mL of water. The organics were washed with 50 mL of brine, dried over Na₂ SO₄ and activated charcoal, concentrated and the residue was recrystallized from EtOAc/hexanes to give 3.3 g (36%) of the title compound: m=221-22° C.; IR (KBr) 3345, 3319, 3155, 1645, 1562 cm⁻¹ ; ¹ H NMR (CDCl₃) δ8.17 (1H, d, J=5.1 Hz), 7.72 (1H, s), 7.45 (2H, m), 7.00 (2H, t, J=8.7 Hz), 6.49 (1H, d, J=5.2 Hz), 5.30 (1H, tt, J=3.2, 12.6 Hz), 5.12 (2H, br s), 2.04 (2H, dd, J=3.2, 12.4 Hz), 1.48 (2H, t, J=12.3 Hz), 1.24 (6H, s), 1.17 (6H, s); ¹³ C NMR (DMSO-d₆) δ163.67, 162.72, 159.49, 158.77, 158.49, 138.68, 135.43, 130.92, 128.93, 128.82, 125.14, 115.09, 114.81, 111.00, 50.81, 48.67, 44.74, 34.06, 28.11. Anal. Calcd for C₂₂ H₂₇ N₆ F: C, 66.98; H, 6.90; N, 21.30. Found C, 67.37; H, 6.88; N, 21.39.

Alternative conditions employed include

    ______________________________________     Solvent DMFDMA temp   Base     Pyrimidine temp.     ______________________________________     DMF     100° C.                           K.sub.2 CO.sub.3                                    120° C.     DMSO    100° C.                           K.sub.2 CO.sub.3                                    100° C.     DMSO    100° C.                           KOH      100° C.     1-PrOH  100° C.                           KOH/H.sub.2 O                                    100° C.     EtOH     85° C.                           NaOMe     85° C.     2-PrOH   85° C.                           NaOMe     85° C.     ______________________________________

In yet another alternative procedure to those listed above, the title compound was prepared in the following manner: To a solution of pyruvaldehyde (40% w/w solution in water, 5.82 mLL, 6.85 g, 38.04 mmol) in 70 mL of DMSO at room temperature was added 2,2,6,6-tetramethyl-4-aminopiperidine (6.52 ml, 5.94 g, 38.04 mmol). After 15-20 min, α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (10 g, 34.6 mmol) and K₂ CO₃ (5.02 g, 36.3 mmol) were added. After 19 h, an HPLC solution assay indicated that 6.79 g (57%) of the ketoimidazole (title compound of Example 8) had formed and that reaction was complete. To the solution was added 30 mL of toluene, and the solution was heated at 65° C. while the toluene was removed under vacuum. The toluene addition/distillation was repeated two times more. N,N-dimethylformamide dimethyl acetal (DMFDMA) (9.2 mL, 8.24 g, 69.2 mmol) was added and the solution was heated at 100° C. After 2 h, HPLC indicated no reaction, so an additional 9.2 mL of DMFDMA were added, and after 15 h an additional 5 mL of DMFDMA were added and heated for 1 h. Guanidine•HCl (6.61 g, 69.2 mmol) and K₂ CO₃ (9.56 g, 69.2 mmol) were added and heated at 100° C. for 6.75 h, at which point HPLC indicated that the reaction was complete. After cooling to room temperature, the solution was filtered through a pad of Celite, diluted with 250 mL of EtOAc and washed with 4×200 mL of 3N HCl. The aqueous layers were combined and basified with solid KOH to pH=14. The aqueous layer was transferred to a separatory funnel and extracted 3×200 mL of EtOAc. The combined organics were washed with 3×100 mL of 3N KOH solution and 50 mL of brine, dried over Na₂ SO₄ and activated charcoal, filtered through Celite and concentrated in vacuo. The residue was dissolved in 50 mL of MeOH and the crystals which formed were filtered and washed with 100 ml of EtOAc to yield the title compound (4.89 g, 36%) as a tan solid.

EXAMPLE 11 1-(1-t-Butoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-acetylimidazole ##STR23##

To a solution of t-butyl 4-amino-piperidinecarboxylate (0.95 g, 4.75 mmol) in 40 mL of Et₂ O was added pyruvaldehyde (40% w/w solution in water, 0.94 mL, 1.11 g, 6.17 mmol) at room temperature. After 1.75 h, the solution was poured into a separatory funnel, diluted with 30 mL of Et₂ O and 10 mL of EtOAc, and washed with 2×10 mL of water. The organics were concentrated in vacuo and the residue was diluted in 10 mL of DMF and α-(p-toluenesulfonyl)-4-fluoro-benzylisonitrile (1.37 g, 4.75 mmol) and K₂ CO₃ (0.72 g, 5.23 mmol) were added. After 16 h, the solution was diluted with 100 mL of water and extracted with 2×40 mL of EtOAc. The combined organics were washed with 3×40 mL of 10% HCl. The aqueous layers were combined and neutralized with excess solid NaHCO₃, then basified with 20 mL of 10% KOH. The aqueous layer was transferred to a separatory funnel and extracted 3×30 mL of EtOAc. The combined organics concentrated in vacuo to yield the imidazole product (0.5 g, 27%): ¹ H NMR (CDCl₃) δ7.74, 7.44 (2H, m), 7.13 (2H, t, J=8.6 Hz), 4.97 (1H, tt, J=3.7, 12.0 Hz), 4.29 (2H, m), 2.88 (2H, m), 2.15 (2H, m) 2.11 (3H, s), 1.78 (2H, dq, 4.2, 12.2 Hz), 1.48 (9H, s).

EXAMPLE 12 1 -Benzyl-4-(2-oxopropylidene)aminopiperidine ##STR24##

To a solution of pyruvaldehyde (40% w/w solution in water, 0.49 mL, 0.57 g, 3.19 mmol) in 10 mL of Et₂ O at room temperature was added dropwise 4-amino-1-benzylpiperidine (0.5 mL, 0.46 g, 2.45 mmol). After 20 min, the solution was diluted with 40 mL of Et₂ O and washed with 2×5 mL of water. The solution was concentrated in vacuo to yield the imine product which was used as such in the subsequent step: ¹ H NMR (CDCl₃) δ7.62 (1H, s), 7.29 (5H, m), 3.53 (2H, s), 3.28 (1H, m), 2.91 (2H, m), 2.38 (3H, s), 2.15 (2H, m), 1.84 (2H, m), 1.69 (2H, m)

EXAMPLE 13 1-(1-Benzyl-4-piperidinyl)-4-(4-fluorophenyl)-5-acetylimidazole ##STR25##

To a solution of the inline described in Example 12 above (assumed 100% yield for Example 12, 0.64 g, 2.44 mmol) in 5 mL of DMF at 0° C. was added α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile (0.85 g, 2.93 mmol) and K₂ CO₃ (0.40 g, 2.93 mmol) and K₂ CO₃ (0.40 g, 2.93 mmol). The solution was stirred at 0° C. for 2 h, then gradually warmed to room temperature over 15 h. The solution was diluted with 70 mL of EtOAc and washed with 100 and 50 mL of water. The organic layer was acidified with 2×55 mL of 3N HCl. The aqueous layers were combined and neutralized with solid NaHCO₃ then basified with 30 mL of 10% KOH. The aqueous layer was transferred to a separatory funnel, extracted with 2×50 mL of EtOAc and concentrated in vacuo to yield the title compound (0.38 g, 41%) which was used in subsequent steps: ¹ H NMR (CDCl₃) δ7.78 (1H, s), 7.43 (2H, m), 7.27 (5H, m), 7.11 (2H, t, J=8.6 Hz), 4.80 (1H, tt, J=3.9, 11.8 Hz), 3.55 (2H, s), 3.02 (2H, d, J=11.9 Hz), 2.16 (2H, m), 2.10 (3H, s), 1.94 (2H, m).

EXAMPLE 14 1-(1-Benzyl-4-piperidinyl)-4-(4-fluorophenyl)-5- 2-(amino)-4-pyrimidinyl!imidazole ##STR26##

To a solution of the ketoimidazole prepared in Example 13 above (0.38 g, 1.01 mmol) in 5 mL of EtOH was added N,N-dimethylformamide dimethyl acetal (0.4 mL, 0.36 g, 3.02 mmol) and the solution was heated at 90° C. for 3 h. After 3 h, an additional 1 mL of DMFDMA was added and heated for 3 h. At this time, TLC indicated no starting material and the solution was cooled to 70° C. and guanidine•HCl (0.19 g, 2.02 mmol) and NaOMe (25% w/w solution, 0.46 mL, 0.44 g, 2.02 mmol) were added. After 15 hours, additional N-methylguanidine•HCl (0.19 g, 2.02 mmol) and NaOMe (25% w/w solution, 0.46 mL, 0.44 g, 2.02 mmol) were added and heated at 75° C. for 24 h. The solution was cooled to room temperature, diluted with 50 mL of water and extracted 2×50 mL of EtOAC. The combined organics were concentrated and the residue was recrystallized from EtOAc to give 0.2 g (47%) of the title compound: ¹ H NMR (CDCl₃) δ8.19 (1H, d, J=5.2 Hz), 7.76 (1H, s), 7.44 (2H, m), 7.33 (5H, m), 7.01 (2H, t J=8.6 Hz), 6.50 (1H, d, J=5.2 Hz), 5.17 (2H, br s), 4.54 (1H, m), 3.53 (2H, s), 3.02 (2H, m), 2.09 (6H, m).

Additional compounds produced using the analogous methods to those indicated above include

Example 15: 5-(2-Phenylamino-4-pyrimdinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole

Example 16: 1- 1-Carbomethoxy)piperidin-4-yl!-4-(4-fluorophenyl)-5- 2- 3-benzylo)phenylamino!pyrimidin-4-!imidazole

Example 17: 1- 1-Carbomethoxy)piperidin-4-yl!-4-(4-fluorophenyl)-5- 2- 4-benzylox)phenylamino!pyrimdin-4-yl!!imidazole

Example 18: 1-(Piperdin-4-yl)-4-(4-fluorophenyl)-5- 2-(3-tifluoromethylphenyl)-amino!pyrimidin-4-yl)imidazole

Example 19: 1-(Piperdin-4-yl)-4-(4-fluorophenyl)-5- 2-(3-4,difluorophenyl)-amino!pyrimidin-4-yl)imidazole

The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the are can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows. 

What is claimed is:
 1. A compound of the formula: ##STR27## wherein R_(b) is an alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl, heterocyclic, or heterocyclicalkyl, all of which are unsubstituted or substituted;R is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, halogen, hydroxyl, thiol, C₁₋₁₀ alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylsulfinyl, CH₂ OR₁₂, amino, mono or di-C₁₋₁₀ alkyl substituted amino, NHR₂₁, N(R₁₀)C(O)R_(a) or an N-heterocyclyl ring which ring has from 5 to 7 members and does not contain or contains an additional heteroatom selected from oxygen, sulfur or NR₁₅ ; R_(a) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄ alkyl; R₄ is an unsubstituted or substituted phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl ring; R₂ is -(CR₁₀ R₂₀)_(n') OR₉, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl, C₅₋₇ cycloalkenyl-C₁₋₁₀ -alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroaryl-C₁₋₁₀ -alkyl, (CR₁₀ R₂₀)_(n) OR₁₁, (CR₁₀ R₂₀)_(n) S(O)_(m) R₁₈, (CR₁₀ R₂₀)_(n) NHS(O)₂ R₁₈, (CR₁₀ R₂₀)_(n) NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NO₂, (CR₁₀ R₂₀)_(n) CN, (CR₁₀ R₂₀)_(n') SO₂ R₁₈, (CR₁₀ R₂₀)_(n) S(O)_(m') NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) C(Z)R₁₁, (CR₁₀ R₂₀)_(n) OC(Z)R₁₁, (CR₁₀ R₂₀)_(n) C(Z)OR₁₁, (CR₁₀ R₂₀)_(n) C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) C(Z)NR₁₁ OR₉, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)R₁₁, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) N(OR₆)C(Z)R₁₁, (CR₁₀ R₂₀)_(n) C(═NOR₆)R₁₁, (CR₁₀ R₂₀)_(n) NR₁₀ C(═NR₁₉)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) OC(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NR₁₀ C(Z)NR₁₃ R₁₄, (CR₁₀ R₂₀)_(n) NR₁₀, C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or 4-(R₁₂)-5-R₁₈ R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl may be unsubstituted or substituted; n is an integer having a value of 1 to 10; n' is 0, or an integer having a value of 1 to 10; m is 0, or the integer 1 or 2; m' is an integer having a value of 1 or 2; Z is oxygen or sulfur; R₆ is hydrogen, a pharmaceutically acceptable cation, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl; R₉ is hydrogen, C(Z)R₁₁ or unsubstituted or substituted C₁₋₁₀ alkyl, S(O)₂ R₁₈, unsubstituted or substituted aryl or unsubstituted or substituted aryl-C₁₋₄ alkyl; R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl; R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl; R₁₂ is hydrogen or R₁₆ ; R₁₃ and R₁₄ is each independently selected from hydrogen or unsubstituted or substituted C₁₋₄ alkyl, unsubstituted or substituted aryl or unsubstituted or substituted aryl-C₁₋₄ alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring does not contain or contains an additional heteroatom selected from oxygen, sulfur or NR₉ ; R₁₅ is R₁₀ or C(Z)-C₁₋₄ alkyl; R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇ cycloalkyl; R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C₁₋₁₀ alkyl, heteroaryl or heteroarylalkyl; R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl; R₂₁ is an alkyl, aryl, arylC₁₋₆ alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl moiety, wherein each of these moieties may be unsubstituted or substituted.
 2. The compound according to claim 1 wherein R₄ is 4-fluorophenyl, and R₂ is an unsubstituted or substituted heterocyclic, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, or C₃₋₇ cycloalkyl C₁₋₁₀ alkyl.
 3. The compound according to claim 2 wherein R is C₁₋₄ alkoxy, C₁₋₄ alkyl thio, or amino.
 4. The compound according to claim 2 wherein R₂ is an unsubstituted or substituted heterocyclic.
 5. The compound according to claim 4 wherein the heterocyclic is a piperidin-4-yl.
 6. The compound 1 according to claim 5 wherein the piperidin-4-yl ring is a 1-ethoxy carbonyl-4-piperidinyl, 1-t-butoxycarboxy-4-piperidinyl, or 1-benzyl-4-piperidinyl. 